Myocardial ischemia and severe arrhythmias have been described in acute systemic allergic reactions in humans. Cardiac hypersensitivity reactions will be elicited in the experimental animal, as a first step in the assessment of cardiac hypersensitivity as a clinical problem. Thus, we will explore in guinea pig, rabbit and monkey heart sensitized to various allergens, the pharmacology of the various mediators of immediate hypersensitivity, i.e., histamine, the various products of arachidonic acid metabolism, slow reacting substance of anaphylaxis (SRS-A) and platelet activating factor (PAF). Human cardiac tissue will also be studied. Models of IgE-mediated cardiac hypersensitivity reactions will be investigated. Concentration-response relationships will be sought between released mediators and the extent of cardiac dysfunction. Alterations in prostacyclin generation by the heart as a result of hypersensitivity will be studied, particularly as this may lead to impairment of coronary vascular homeostasis or to thrombus formation. Interactions between released mediators and various disease states and drugs, i.e., myocardial ischemia, hypertension, hyperthyroidism, digitalis, diuretics, will be investigated. Pharmacologic means will be sought for correcting and controlling the cardiac dysfunctions caused by immediate hypersensitivity reactions. It will also be ascertained whether autacoid release, particularly histamine, may be physiologically involved in the regulation of cardiac sympathetic function. The pathophysiologic interactions of histamine with ischemic arrhythmias, digitalis toxicity and hyperthyroidism will also be examined. Since histamine can be released at any site by any means, this work will define cardiac responses to a major autacoid. In so doing, the research should uncover hitherto unknown mechanisms of common cardiovascular diseases.